NM_000303.3(PMM2):c.710C>G (p.Thr237Arg) AND PMM2-congenital disorder of glycosylation

Germline classification:: Pathogenic/Likely pathogenic (14 submissions)
Last evaluated:: Dec 23, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000008155.48

Allele description [Variation Report for NM_000303.3(PMM2):c.710C>G (p.Thr237Arg)]

NM_000303.3(PMM2):c.710C>G (p.Thr237Arg)

Gene:

PMM2:phosphomannomutase 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16p13.2

Genomic location:

Preferred name:

NM_000303.3(PMM2):c.710C>G (p.Thr237Arg)

HGVS:

NC_000016.10:g.8847794C>G
NG_009209.1:g.54982C>G
NM_000303.3:c.710C>GMANE SELECT
NP_000294.1:p.Thr237Arg
NP_000294.1:p.Thr237Arg
NC_000016.9:g.8941651C>G
NM_000303.2:c.710C>G
O15305:p.Thr237Arg

Protein change:

T237R; THR237ARG

Links:

UniProtKB: O15305#VAR_022508; OMIM: 601785.0011; dbSNP: rs80338708

NCBI 1000 Genomes Browser:

rs80338708

Molecular consequence:

NM_000303.3:c.710C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: PMM2-congenital disorder of glycosylation
Synonyms:: CDG Ia; JAEKEN SYNDROME; PHOSPHOMANNOMUTASE 2 DEFICIENCY; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008907; MedGen: C0349653; Orphanet: 79318; OMIM: 212065

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000028360	OMIM	no assertion criteria provided	Pathogenic (Dec 1, 1999)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000399682	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Apr 27, 2017)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 9497260, 15844218, 10602363, 11156536, 15714316, 27415628 Citation Link,
SCV000696503	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Sep 9, 2016)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15844218, 9497260, 25355454 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV000894096	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 31, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000958650	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 23, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 25355454, 25497157, 10602363, 9497260, 11156536, 11589167, 11891694, 15714316, 28492532
SCV000998572	Pediatric Metabolic Diseases, Hacettepe University	criteria provided, single submitter (International clinical guidelines for PMM2-CDG, 2019)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001163407	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 27, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001194151	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Likely pathogenic (Jan 6, 2020)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 10602363, 17920054, 25355454, 11058895 Citation Link,
SCV001366369	Centre for Mendelian Genomics, University Medical Centre Ljubljana	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 1, 2016)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001425247	Molecular Biology Laboratory, Fundació Puigvert - KidneyPanel_2020	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 1, 2020)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 33532864
SCV002018865	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 24, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002092452	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 23, 2017)	germline	clinical testing
SCV002577413	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 28, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004013625	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 28139241, 10602363, 9497260, 9140401, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing, research
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Natural Killer Cell Receptors and Cytotoxic Activity in Phosphomannomutase 2 Deficiency (PMM2-CDG).

García-López R, de la Morena-Barrio ME, Alsina L, Pérez-Dueñas B, Jaeken J, Serrano M, Casado M, Hernández-Caselles T.

PLoS One. 2016;11(7):e0158863. doi: 10.1371/journal.pone.0158863. Erratum in: PLoS One. 2016 Oct 27;11(10):e0165901. doi: 10.1371/journal.pone.0165901..

PubMed [citation]

PMID:: 27415628
PMCID:: PMC4944953

A new insight into PMM2 mutations in the French population.

Le Bizec C, Vuillaumier-Barrot S, Barnier A, Dupré T, Durand G, Seta N.

Hum Mutat. 2005 May;25(5):504-5.

PubMed [citation]

PMID:: 15844218

See all PubMed Citations (18)

PMC

Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From OMIM, SCV000028360.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a patient with congenital disorder of glycosylation type I (CDG1A; 212065), Kjaergaard et al. (1999) identified a thr237-to-arg substitution (T237R) in the PMM2 gene. The patient was a compound heterozygote for the asp223-to-glu substitution (601785.0009).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV000399682.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

The PMM2 c.710C>G (p.Thr237Arg) missense variant has been reported in at least six studies in which it is found in a total of nine patients with congenital disorders of glycosylation type 1a, all of whom were in a compound heterozygous state with either one or two other missense variants (Matthijs et al. 1998; Kjaergaard et al. 1999; GrÃ¼newald et al. 2001; Aronica et al. 2005; Le Bizec et al. 2005; GarcÃa-LÃ³pez et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.00027 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in E.coli showed that the variant protein was produced in similar quantities compared to wild type and was present in the same subcellular fraction but had no detectable catalytic activity (Kjaergaard et al. 1999). Based on the collective evidence, the p.Thr237Arg variant is classified as pathogenic for congenital disorders of glycosylation type 1a. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696503.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: The PMM2 c.710C>G (p.Thr237Arg) variant causes a missense change involving a conserved nucleotide with 5/5 in silico tools predicting a "damaging" outcome, which PMM2 activity detection levels support this. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 18/120616 (1/6702), which does not exceed the estimated maximal expected allele frequency for a pathogenic PMM2 variant of 1/178. Multiple publications report the variant in compound heterozygote and homozygote affected individuals. In addition, multiple reputable databases and clinical diagnostic laboratories cite the variant as "pathogenic." Therefore, the variant of interest has been classified as "pathogenic."

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV000894096.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000958650.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 237 of the PMM2 protein (p.Thr237Arg). This variant is present in population databases (rs80338708, gnomAD 0.03%). This missense change has been observed in individuals with PMM2-CDG (PMID: 9497260, 10602363, 15714316, 25355454, 25497157). ClinVar contains an entry for this variant (Variation ID: 7716). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PMM2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PMM2 function (PMID: 10602363). This variant disrupts the p.Thr237 amino acid residue in PMM2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9497260, 11156536, 11589167, 11891694, 15714316). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Pediatric Metabolic Diseases, Hacettepe University, SCV000998572.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV001163407.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV001194151.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

NM_000303.2(PMM2):c.710C>G(T237R) is classified as likely pathogenic in the context of congenital disorder of glycosylation type Ia. Sources cited for classification include the following: PMID 10602363, 17920054, 25355454 and 11058895. Classification of NM_000303.2(PMM2):c.710C>G(T237R) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Centre for Mendelian Genomics, University Medical Centre Ljubljana, SCV001366369.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PP3,PP5.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Molecular Biology Laboratory, Fundació Puigvert - KidneyPanel_2020, SCV001425247.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002018865.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV002092452.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory of Medical Genetics, National & Kapodistrian University of Athens, SCV002577413.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

PS4, PM1, PM2, PM5, PP2, PP3, PP5

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From 3billion, SCV004013625.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (5)

Description

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.014%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 10602363). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.98; 3Cnet: 0.92). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000007716 / PMID: 9497260). Different missense changes at the same codon (p.Thr237Lys, p.Thr237Met) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000021145 / PMID: 28139241, 9140401). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Jul 5, 2025

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